The proposed Specialized Center of Research on Coronary Heart Disease is a broad laboratory and clinical research effort focused on the general goal of elucidating mechanisms of myocardial cell injury, adaptive responses to ischemia and infarction over time, and approaches for modifying and reversing the injurious effects of coronary heart disease. Mechanisms of ischemic cell injury will be explored by studying beta-adrenergic receptor properties and post-receptor mechanisms, G protein expression studied being by cDNA probes; Na+ channel gene expression in ischemia and hypertrophied myocardium, with in situ hybridization techniques to assess their distribution; heat shock protein (HSP) expression, and its potential protective effect and appearance of other mRNAs in ischemic and infarcted tissue; the injurious effects of leukocytes and mechanisms by which their activation can be studied in microcirculatory and intact animal models, with clinical studies on the predictive value of the activated leukocyte pool size; of the pre- and post-synaptic alpha1 and alpha2 receptor activation and blockade on the coronary vessels and myocardium, particularly in exercise-induced ischemia. Studies on adaptive responses will include mechanisms involved in the recovery of left ventricular function after experimental coronary occlusion and reperfusion, in particular the role of stunning and subsequent hypertrophy studied by mRNA markers of contractile protein synthesis; changes in the beta receptor life cycle and Na+ channel late after coronary occlusion with reperfusion; the mechanical effects of infarction and later scarring on finite left ventricular strains; regional stress effects on myocardial blood flow, and alterations in the collagen matrix and applications of NMR spectroscopy, including a chronically instrumented animal model allowing long and applications of NMR spectroscopy, including a chronically instrumented animal model allowing long term 31P spectroscopy studies, and advanced mechanisms to investigate other metabolites. Approaches for modifying or reversing effects of coronary heart disease will include experimental studies on improving the recovery of regional myocardial function after reperfusion; investigations on the effects of lowering the serum cholesterol on functional coronary reactivity and anatomy using digital imaging techniques in patients with coronary heart disease; the role of coronary angiography following acute myocardial infarction, and identification of high risk patients with depressed cardiac function who have dysfunctional but viable zones using positron emission tomographic imaging (PET). In an expanded UCSD SCOR Postinfarction Database, prospective studies across countries (United States, Canada, and Sweden) with widely differing management strategies, will use descriptive and analytic studies to examine outcomes and cost-effectivenesses of various diagnostic and therapeutic approaches in patient substrata, using a cost- effectivenesses of various diagnostic and therapeutic approaches in patient substrata, using a multivariate risk stratification scheme. This interdepartmental program will bring the disciplines of molecular biology, pharmacology, cardiovascular physiology, bioengineering, epidemiology, pathology and cardiology, together with their associated technologies, to bear on the solution of these significant problems in the pathogenesis and therapy of coronary heart disease.